SR-BI-mediated selective lipid uptake segregates apoA-I and apoA-II catabolism

Abstract

The HDL receptor scavenger receptor class B type I (SR-BI) binds HDL and mediates the selective uptake of cholesteryl ester. We previously showed that remnants, produced when human HDL 2 is catabolized in mice overexpressing SR-BI, become incrementally smaller, ultimately consisting of small ␣ -migrating particles, distinct from pre ␤ HDL. When mixed with mouse plasma, some remnant particles rapidly increase in size by associating with HDL without the mediation of cholesteryl ester transfer protein, LCAT, or phospholipid transfer protein. Here, we show that processing of HDL 2 by SR-BI-overexpressing mice resulted in the preferential loss of apolipoprotein A-II (apoA-II). Short-term processing generated two distinct, small ␣ -migrating particles. One particle (8.0 nm diameter) contained apoA-I and apoA-II; the other particle (7.7 nm diameter) contained only apoA-I. With extensive SR-BI processing, only the 7.7 nm particle remained. Only the 8.0 nm remnants were able to associate with HDL. Compared with HDL 2 , this remnant was more readily taken up by the liver than by the kidney. We conclude that SR-BI-generated HDL remnants consist of particles with or without apoA-II and that only those containing apoA-II associate with HDL in an enzyme-independent manner. Extensive SR-BI processing generates small apoA-II-depleted particles unable to reassociate with HDL and readily taken up by the liver. This represents a pathway by which apoA-I and apoA-II catabolism are segregated.

SR-BI Selective Lipid Uptake

“…The production of SR-BI-generated HDL remnants in apoA-I -/- mice was described (6, 7, 8). ApoA-I -/- mice weighing at least 25 g were tail vein injected with 1.5 × 10 11 particles AdSR-BI, a replication-defective adenoviral vector expressing mouse SR-BI, or Adnull, a control vector containing no transgene.…”

“…After incubations at 37° C, the remodeling reactions were transferred to ice, mixed with an equal volume of saturated sucrose, and immediately applied to a non-denaturing gradient gel and visualized by autoradiography (7, 8). …”

“…SR-BI-mediated selective lipid uptake generates incrementally smaller and denser HDL particles (HDL remnants) (6). With respect to normal human HDL, these remnants are not rapidly cleared from the circulation but rather remodel to form large HDL particles by association with existing lipoprotein particles, preferably HDL (6, 7, 8). A portion of the HDL remnant apolipoproteins is directed toward catabolism (9).…”

“…The first is an established model where the metabolic fate of radiolabeled AP HDL in mice over expressing SR-BI is evaluated (6, 7, 8). The second involves monitoring the effect of dual SR-BI and SAA adenoviral expression on endogenous HDL metabolism.…”

Determinants of plasma HDL concentrations and reverse cholesterol transport

“…SR-B1 does not appear to generate pre-b HDL. Extensive SR-B1 processing also generates small apoAII-depleted particles unable to reassociate with HDL and readily taken up by the liver [51]. Recent studies using adenovirus-mediated CETP expression in primary mouse hepatocytes suggests that CETP also plays an important role in selective cholesteryl ester uptake by the liver, independently of other known lipoprotein receptors [52 ].…”